Bottom Line:
In the present study, trigeminal neuropathy was induced by chronic constrictive nerve injury of the infraorbital nerve (ION-CCI).Testing animals performed operant tasks by voluntarily contacting their orofacial regions to a cold stimulation module in order to access sweetened milk as a reward, and contact time and number of the operant behaviors were automatically recorded.The behavioral outcomes support the idea that TRPM8 plays a role in cold allodynia and hyperalgesia following chronic trigeminal nerve injury.

Affiliation: Department of Anesthesiology and the Graduate Program in Neuroscience, The University of Cincinnati College of Medicine, Cincinnati, OH 45267-0531, USA.

ABSTRACTBoth spinal and trigeminal somatosensory systems use the TRPM8 channel as a principal transducer for detecting cold stimuli. It is currently unclear whether this cold transducer may play a role in trigeminal neuropathic pain manifesting cold allodynia and hyperalgesia. In the present study, trigeminal neuropathy was induced by chronic constrictive nerve injury of the infraorbital nerve (ION-CCI). Behavioral responses to cold stimuli in orofacial regions were assessed by the newly developed orofacial operant test in the ION-CCI rats. We tested menthol and capsazepine, two compounds that can activate and inhibit TRPM8 respectively, on orofacial operant responses to cold stimuli in ION-CCI rats. Testing animals performed operant tasks by voluntarily contacting their orofacial regions to a cold stimulation module in order to access sweetened milk as a reward, and contact time and number of the operant behaviors were automatically recorded. Total contact time was significantly reduced at the cooling temperatures of 17°C and 12°C in ION-CCI group in comparison with sham group, indicating the presence of cold allodynia and hyperalgesia in ION-CCI rats. When menthol was administered to ION-CCI rats, total contact time was further reduced and total contact number increased at the cooling temperatures. In contrast, after administration of capsazepine to ION-CCI rats, total contact time was significantly increased at the cooling temperatures. The behavioral outcomes support the idea that TRPM8 plays a role in cold allodynia and hyperalgesia following chronic trigeminal nerve injury.

Mentions:
We then tested effects of the same dose of capsazepine (3 mg/kg) on orofacial operant behaviors in ION-CCI rats to see if cold hypersensitivity of these chronic trigeminal nerve-injured rats could be alleviated by the TRPM8 antagonist. At 24°C, total contact time was comparable between capsazepine-injected group (304.7±24.3 s, n=7) and vehicle injection group (281.4±24.3 s, n=7) (Figure 4A). However, total contact time was significantly longer in capsazepine-injected group than in vehicle-injected group at 17°C or 12°C. At 17°C, the total contact time was 205.0±28.2 s (n=6) in vehicle-injected group and increased to 293.6±15.5 s (n=6) in capsazepine-injected group (Figure 4B, P <0.05). At 12°C, the total contact time was 61.2±7.5 s (n=6) in vehicle-injected group and increased to 108.7±16.8 s (n=6) in capsazepine-injected group (Figure 4C, P<0.01). While total contact time was increased by capsazepine in ION-CCI rats, total contact number in these animals was not significantly different between capsazepine-injected group and vehicle-injected group at each temperature tested. At 24°C, total contact number was 70.6±18.4 (n=7) in capsazepine-injected group and 60.3±14.6 (n=7) in vehicle-injected group (Figure 4D). At 17°C, total contact number was 93.0±15.5 (n=6) in capsazepine-injected group and 97.5±12.7 (n=6) in vehicle-injected group (Figure 4E). At 12°C, total contact number was 108.7±16.8 (n=6) in capsazepine-injected group and 99.2±13.8 (n=6) in vehicle-injected group (Figure 4F). Because total contact time but not total contact number was modified by capsazepine in ION-CCI rats, we further examined cumulative contact time during the course of 10-min orofacial operant tests (Figure 5). At 24°C, capsazepine-injected rats and vehicle control had similar cumulative contact time at each time point (Figure 5A, n=7). In contrast, at both 17°C (Figure 5B, n=7) and 12°C (Figure 5C, n=7), cumulative contact time at most time points was significantly longer in capsazepine-injected group than in vehicle control group.

Mentions:
We then tested effects of the same dose of capsazepine (3 mg/kg) on orofacial operant behaviors in ION-CCI rats to see if cold hypersensitivity of these chronic trigeminal nerve-injured rats could be alleviated by the TRPM8 antagonist. At 24°C, total contact time was comparable between capsazepine-injected group (304.7±24.3 s, n=7) and vehicle injection group (281.4±24.3 s, n=7) (Figure 4A). However, total contact time was significantly longer in capsazepine-injected group than in vehicle-injected group at 17°C or 12°C. At 17°C, the total contact time was 205.0±28.2 s (n=6) in vehicle-injected group and increased to 293.6±15.5 s (n=6) in capsazepine-injected group (Figure 4B, P <0.05). At 12°C, the total contact time was 61.2±7.5 s (n=6) in vehicle-injected group and increased to 108.7±16.8 s (n=6) in capsazepine-injected group (Figure 4C, P<0.01). While total contact time was increased by capsazepine in ION-CCI rats, total contact number in these animals was not significantly different between capsazepine-injected group and vehicle-injected group at each temperature tested. At 24°C, total contact number was 70.6±18.4 (n=7) in capsazepine-injected group and 60.3±14.6 (n=7) in vehicle-injected group (Figure 4D). At 17°C, total contact number was 93.0±15.5 (n=6) in capsazepine-injected group and 97.5±12.7 (n=6) in vehicle-injected group (Figure 4E). At 12°C, total contact number was 108.7±16.8 (n=6) in capsazepine-injected group and 99.2±13.8 (n=6) in vehicle-injected group (Figure 4F). Because total contact time but not total contact number was modified by capsazepine in ION-CCI rats, we further examined cumulative contact time during the course of 10-min orofacial operant tests (Figure 5). At 24°C, capsazepine-injected rats and vehicle control had similar cumulative contact time at each time point (Figure 5A, n=7). In contrast, at both 17°C (Figure 5B, n=7) and 12°C (Figure 5C, n=7), cumulative contact time at most time points was significantly longer in capsazepine-injected group than in vehicle control group.

Bottom Line:
In the present study, trigeminal neuropathy was induced by chronic constrictive nerve injury of the infraorbital nerve (ION-CCI).Testing animals performed operant tasks by voluntarily contacting their orofacial regions to a cold stimulation module in order to access sweetened milk as a reward, and contact time and number of the operant behaviors were automatically recorded.The behavioral outcomes support the idea that TRPM8 plays a role in cold allodynia and hyperalgesia following chronic trigeminal nerve injury.

Affiliation:
Department of Anesthesiology and the Graduate Program in Neuroscience, The University of Cincinnati College of Medicine, Cincinnati, OH 45267-0531, USA.

ABSTRACTBoth spinal and trigeminal somatosensory systems use the TRPM8 channel as a principal transducer for detecting cold stimuli. It is currently unclear whether this cold transducer may play a role in trigeminal neuropathic pain manifesting cold allodynia and hyperalgesia. In the present study, trigeminal neuropathy was induced by chronic constrictive nerve injury of the infraorbital nerve (ION-CCI). Behavioral responses to cold stimuli in orofacial regions were assessed by the newly developed orofacial operant test in the ION-CCI rats. We tested menthol and capsazepine, two compounds that can activate and inhibit TRPM8 respectively, on orofacial operant responses to cold stimuli in ION-CCI rats. Testing animals performed operant tasks by voluntarily contacting their orofacial regions to a cold stimulation module in order to access sweetened milk as a reward, and contact time and number of the operant behaviors were automatically recorded. Total contact time was significantly reduced at the cooling temperatures of 17°C and 12°C in ION-CCI group in comparison with sham group, indicating the presence of cold allodynia and hyperalgesia in ION-CCI rats. When menthol was administered to ION-CCI rats, total contact time was further reduced and total contact number increased at the cooling temperatures. In contrast, after administration of capsazepine to ION-CCI rats, total contact time was significantly increased at the cooling temperatures. The behavioral outcomes support the idea that TRPM8 plays a role in cold allodynia and hyperalgesia following chronic trigeminal nerve injury.